Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis

In cancer cells, glucose is often converted into lactic acid,which is known as the ‘Warburg effect’. The reason thatcancer cells have a higher rate of aerobic glycolysis, butnot oxidative phosphorylation, remains largely unclear.Herein, we proposed an epigenetic mechanism of theWarburg effect. Fructose-1,6-bisphosphatase-1 (FBP1),which functions to antagonize glycolysis was downregu-lated through NF-kappaB pathway in Ras-transformedNIH3T3 cells. Restoration of FBP1 expression sup-pressed anchorage-independent growth, indicating therelevance of FBP1 downregulation in carcinogenesis.Indeed, FBP1 was downregulated in gastric carcinomas(Po0.01, n¼22) and gastric cancer cell lines (57%, 4/7).Restoration of FBP1 expression reduced growth andglycolysis in gastric cancer cells. Moreover, FBP1 down-regulation was reversed by pharmacological demethyla-tion. Its promoter was hypermethylated in gastric cancercell lines (57%, 4/7) and gastric carcinomas (33%, 33/101). Inhibition of NF-kappaB restored FBP1 expression,partially through demethylation of FBP1 promoter.Notably, Cox regression analysis revealed FBP1 promo-ter methylation as an independent prognosis predicator forgastric cancer (hazard ratio: 3.60, P¼0.010). In sum-mary, we found that NF-kappaB functions downstream ofRas to promote epigenetic downregulation of FBP1.Promoter methylation of FBP1 can be used as a newbiomarker for prognosis prediction of gastric cancer. Suchan important epigenetic link between glycolysis andcarcinogenesis partly explains the Warburg effect.Oncogene advance online publication, 2 November 2009;doi:10.1038/onc.2009.332Keywords: methylation; gastric cancer; glucose meta-bolism; rasIntroductionIn mammalian cells, there are two main ways togenerate energy in the form of adenosine triphosphatefrom glucose, oxidative phosphorylation and glycolysis.Oxidative phosphorylation occurs in the mitochondriawith carbon dioxide and water as end products, whereasglycolysis from glucose to lactic acid takes place in thecytoplasm. Glycolysis is usually inhibited in the presenceof oxygen, which is termed as the Pasteur effect(DeBerardinis et al., 2008a,b). However, in some patho-logic circumstances such as carcinogenesis, glucose willbe metabolized into lactic acid instead of carbon dioxideand water even in the presence of oxygen, which isknown as the Warburg effect (Warburg, 1956; Gatenbyand Gillies, 2004; Deberardinis et al., 2008a,b).Several decades ago, Otto Warburg found that tumorcells consume glucose at a surprisingly higher rate thannormal cells and most of the glucose-derived carbonwere converted into lactate instead of carbon dioxide(Warburg, 1956). Unfortunately, interest in the rele-vance of the Warburg effect has only been rekindleduntil recently after the successful application of theimaging technique positronemission tomography usingthe glucose analog